New drugs are urgently needed for safe and effective chemotherapy of widespread human diseases like malaria and cancer. We are blending chemical insights and synthesis skills with biological testing in vitro and then, for the most promising new chemical entities, in vivo to establish efficacy and safety. This interdisciplinary research characterizes our program at Hopkins for practical preclincial development of new drug candidates for chemotherapy of malaria and cancer. We are partnering with industry to move one or two of our lead peroxides along the drug development path. Based on our good mechanistic and synthetic progress with anti-infective and anticancer peroxides like the natural trioxane artemlslnin and some of its dimers, we propose the following research goals for the next flve years:. 1.. To continue to design, prepare, and evaluate new, structurally simple, easily prepared, inexpensive, potent and safe dimeric synthetic endoperoxides; 2. To continue lead optimization in developing safe and selective new semi-synthetic trioxanes having both antimalarial and anticancer activities, starting with (a) dihydroartemisinin acetate (b) artemisinin-9-en-lO-aldehyde; 3. To continue exploring mechanism of antimalarial and anticancer action of our most promising peroxides. As synthetic and medicinal chemists, we are in a unique position to make fundamental advances in molecular parasitology and oncology specifically concerning mechanism of action and improved therapeutic aspects of easily prepared and relatively inexpensive new peroxides as antimalarial and anticancer drug candidates. Progress covering 2006-2009 on NIH R37-AI-34885 and plans for 2011-2015 are detailed on the following pages.